We propose a novel pharmacological strategy for treating alcohol and nicotine dependence concomitantly. The reinforcing effects of both alcohol and nicotine are mediated through the cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances their pharmacological effects. We propose a better approach to control dopamine (DA) effects by contemporaneous indirect modulation of DA release and its functional expression. Both DA release from its cell bodies in the ventral tegmental area and the expression of its reinforcing effects through the cortico-mesolimbic system are modulated by GABA efferents under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic function and inhibits glutamate action should diminish both nicotine's and alcohol's reinforcing effects by inhibiting the release of midbrain DA and its functional expression through pathways projecting from the nucleus accumbens to the cortex. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate compared with placebo significantly improved smoking abstinence rates and decreased serum cotinine levels among alcohol- dependent smokers. An important clinical effect of topiramate in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the gradual tapering of drinking. Hence, due to this unique anti- withdrawal effect of topiramate, we propose to adopt the same methodology for treating alcohol-dependent individuals, as is common practice with smokers, of setting a target quit date (TQD) after which relapse to either drug can be measured. We propose an 18-week, double-blind clinical trial with a 3-month follow-up, in which alcohol-dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as their psychosocial treatment, and will be randomized to receive placebo, high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a total N of 294. The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is to determine whether both low- and high-dose topiramate will be more efficacious than placebo at reducing the percentage of heavy drinking days and increasing the continuous abstinence rate for smoking determined by a combination of self-report and CO monitoring after the TQD and in the last 4 weeks of treatment. We also will be able to determine whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is associated with a lower adverse profile. Our secondary objectives are to test whether topiramate will be more efficacious than placebo at improving quality of life and reducing craving after the TQD and in the last 4 weeks of treatment and whether this improvement will be sustained in the follow-up phase. PUBLIC HEALTH RELEVANCE: Smokers who are dependent on alcohol have perhaps the highest rate of preventable morbidity and mortality in the U.S. There is compelling evidence that promoting smoking cessation among those with alcohol dependence not only increases the likelihood of abstinence from smoking but also reduces drinking behavior. Few pharmacotherapy studies have sought medicines that are efficacious at treating both alcohol and nicotine dependence. We have provided evidence that topiramate, a facilitator of 3-aminobutyric acid (GABA) and an inhibitor of AMPA/kainate glutaminergic activity, not only decreased heavy drinking but also diminished nicotine consumption among a cohort of alcohol-dependent individuals who smoked. We now propose to test the efficacy of topiramate in a trial that focuses on treating alcohol-dependent smokers concomitantly. The uniqueness of the proposed trial is that it will include behavioral measures specifically focused to enhance smoking abstinence, address the treatment of both comorbid disorders equally in its general approach, and be directly comparable to the reporting of smoking cessation studies in its design by using a target quit date. This project supports NIAAA's mission to develop efficacious medications for the treatment of alcohol and nicotine dependence to prevent morbidity and deaths in society.